Obesity has reached epidemic proportions, accounting for increased morbidity, disability, health care expenditures, and mortality. Certain metabolic and comorbid conditions disproportionately affect women. Unfortunately, nonsurgical options for treatment are limited. Knowledge accrued over the past 2 decades regarding physiological and hormonal determinants of weight regulation has contributed to growing evidence regarding efficacious behavioral, dietary, and pharmacologic treatments. In this review, the biology of excess adiposity is summarized in the context of a shifting paradigm, approaching obesity as a chronic metabolic disease. Relevant updates are discussed regarding long-term lifestyle approaches and novel drug therapies, with attention to some issues specific to women.